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The decisive etiology of oral squamous cell carcinoma (OSCC) is still ambiguous, but we recognize the contribution of genetic aberration and environmental agents due to OSCC initiation. In the current study, we elucidate the potential impact of EGFR gene polymorphisms on the risk of OSCC in Southeast Iran. Forty-eight OSCC patients along with 100 healthy volunteers were included. Three polymorphisms of the EGFR gene (rs2227983, rs2293347 and rs2227984) were genotype by Tetra-ARMS PCR. Data were analyzed with a chi-square test, and p0.05 was considered s